Project Summary/Abstract There is a pressing need to identify molecular pathways underpinning the acute effects of mild traumatic brain injury (mTBI) and sport-related concussion (SRC). This information will ultimately lead to the development of objective, prognostic biomarkers to enable a more evidence-based approach to the clinical management of mTBI/SRC. Inflammatory cytokines known to be elevated following brain injury lead to the production of kynurenine pathway (KP) metabolites that have neuroprotective or neurotoxic effects on the brain. The effects of SRC on KP metabolites and their inflammatory mediators, however, remain unknown. The objective of this exploratory R21 proposal is to evaluate one potential pathophysiological mechanism behind acute brain and behavioral changes following SRC. The central hypothesis is that SRC leads to inflammation-induced increases in neurotoxic KP metabolites that are associated with short-term changes in behavior and functional connectivity of the hippocampus and medial prefrontal cortex (mPFC). The rationale for this research is that understanding metabolic changes following SRC will aid development of prognostic biomarkers and eventual development of therapeutic strategies for patients with SRC. To test our hypotheses, we will leverage blood, clinical, and neuroimaging data from an existing federally funded project on high school and collegiate athletes. Clinical data and blood is available at pre-injury baseline and at 6 hours, 2 days, 8 days, 15 days, and 45 days post-injury in football players. Neuroimaging data is available at 2, 8, 15, and 45 days post-injury. Non-injured football players with identical time points serve as controls and non-contact sport athletes with identical time points serve as additional controls. We will address the following specific aims: 1) Prospectively establish the time course of changes in neurotoxic KP metabolites and their inflammatory mediators from pre- to multiple post-concussion visits, 2) Determine the extent to which these metabolites are associated with post- concussion symptom reporting and outcome, and 3) Determine the extent to which these metabolites are associated with changes in functional connectivity of the mPFC and hippocampus. This proposal represents a scientifically innovative approach to study SRC by prospectively investigating the role of a well-described metabolic pathway as a potential final common pathway in the pathogenesis of the acute effects of SRC. This exploratory R21 is significant because it will stimulate a new line of programmatic research aimed at identifying physiological targets for therapeutic treatment of SRC.